The present invention relates to compounds having pharmaceutical properties, and in particular, to compounds useful for preventing and treating central nervous system (CNS) disorders. The present invention also relates to compositions of matter useful as pharmaceutical compositions in the prevention and treatment of CNS disorders which have been attributed to neurotransmitter system dysfunction. The present invention more particularly relates to a method for providing certain compounds exhibiting nicotinic pharmacology.
CNS disorders are a type of neurological disorder. CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology. CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency. CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
Nicotine has been proposed to have a number of pharmacological effects. Certain of those effects may be related to effects upon neurotransmitter release. See, for example, Sjak-shie et at., Brain Res., Vol. 624, pp. 295-298 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem., Vol. 43, pp. 1593-1598 (1984); Rapier et al., J. Neurochem., Vol. 50, pp. 1123-1130 (1988); Sandor et al., Brain Res., Vol. 567, pp. 313-316 (1991) and Vizi, Br. J. Pharmacol., Vol. 47, pp. 765-777 (1973). Release of norepinephrine by neurons upon administration of nicotine has been reported by Hall et al., Biochem. Pharmacol., Vol. 21, pp. 1829-1838 (1972). Release of serotonin by neurons upon administration of nicotine has been reported by Hery et al., Arch. Int. Pharmacodyn. Ther., Vol. 296, pp. 91-97 (1977). Release of glutamate by neurons upon administration of nicotine has been reported by Toth et al., Neurochem Res., Vol. 17, pp. 265-271 (1992). Therefore, it would be desirable to provide a pharmaceutical composition containing an active ingredient having nicotinic pharmacology, which pharmaceutical composition is capable of illiciting neurotransmitter release within a subject in order to prevent or treat a neurological disorder. In addition, nicotine reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain CNS disorders. See, Sanberg et al., Pharmacol. Biochem. & Behavior, Vol. 46, pp. 303-307 (1993); Harsing et al., J. Neurochem., Vol. 59, pp. 48-54 (1993) and Hughes, Proceedings from Intl. Symp. Nic., S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed. See, Decina et al., Biol. Psychiatry, Vol. 28, pp. 502-508 (1990); Wagner et al., Pharmacopsychiatry, Vol. 21, pp. 301-303 (1988); Pomerleau et al., Addictive Behaviors, Vol. 9, p. 265 (1984); Onaivi et al., Life Sci., Vol. 54(3), pp. 193-202 (1994) and Hamon, Trends in Pharmacol. Res., Vol. 15, pp. 36-39.
It also has been proposed that nicotine can act directly to elicit the release of acetylcholine in brain tissue, to improve cognitive functions, and to enhance attention. See, Warburton et al., Cholinergic control of cognitive resources, Neuropsychobiology, Eds. Mendlewicz, et al., pp 43-46 (1993); Rowell, et al., J. Neurochem., Vol. 43, p. 1593 (1984); Sherwood, Human Psychopharm., Vol. 8, pp. 155-184 (1993); Hodges, et al., Bio. of Nic., Edit. by Lippiello, et al., p. 157 (1991); Sahakian, et al., Br. J. Psych., Vol. 154, p. 797 (1989); and U.S. Pat. No. 4,965,074 to Leeson and U.S. Pat. No. 5,242,935 to Lippiello et al. It also has been proposed that nicotine pharmacology is beneficial in suppressing the symptoms associated with certain disorders. See, Devor et al., The Lancet, Vol. 8670, p. 1046 (1989); Jarvik, British J. of Addiction, Vol. 86, pp. 571-575 (1991); McConville et al., Am. J. Psychiatry., Vol. 148 (6), pp. 793-794 (1991); Newhouse et al., Brit. J. Addic., Vol. 86, pp. 521-526 (1991); McConville et al., Biol. Psychiatry, Vol. 31, pp. 832-840 (1992); Sanberg et al., Proceedings from Intl. Symp. Nic., S39 (1994); Merriam et al., Psychiatr. Annals, Vol. 23, pp. 171-178 (1993) and Adler et al., Biol. Psychiatry, Vol. 32, pp. 607-616 (1992).
Methods for treating various CNS disorders using (E)-metanicotine-type compounds have been proposed. See, U.S. Pat. No. 5,212,188 to Caldwell et al., Bencherif et al., Soc. for Neurosci., 25th Ann. Mtg. (1995) and Lippiello et al., Soc. for Neurosci., 25th Ann. Mtg. (1995). Methods for the preparation of metanicotine and related compounds have been set forth in Pinner, Chem. Ber., pp. 2861-2370 (1894), Loffler et al., Chem. Ber., Vol. 42, pp. 3431-3438 (1909), Laforge, J.A.C.S., Vol. 50, p. 2477 (1928), Sprouse et al., Abstracts of Papers, p. 32, CORESTA/TCRC Joint Conference (1972), Frank et al., J. Org. Chem., Vol. 43(15), pp. 2947-2949 (1978), Acheson et al., J. Chem. Soc., Perkin Trans. 1, Vol. 2, pp. 579-585 (1980), Malek et al., J. Org. Chem., Vol. 47, pp. 5395-5397 (1982), Cooper et al, Biol. Mass Spectrom., Vol. 22, pp. 590-594 (1993) and U.S. patent application Ser. No. 08/364,979, filed Jan. 6, 1995.
It would be beneficial to provide individuals suffering from certain CNS disorders with interruption of the symptoms of those diseases by the administration of a pharmaceutical composition which has nicotinic pharmacology and which has a beneficial effect upon the functioning of the CNS, but which does not provide any significant associated side effects (e.g., increased heart rate and blood pressure) attendant with interaction of that compound with cardiovascular sites. It would be desirable to provide a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors which have the potential to affect the functioning of the CNS, but which does not significantly affect those receptors which have the potential to induce undesirable side effects (e.g., appreciable pressor cardiovascular effects and appreciable activity at skeletal muscle sites). It would be highly desirable to provide a useful method for providing a nicotinic compound useful for the prevention and treatment of a CNS disorder.